The nuclear hormone receptor superfamily (NHR) and ligand regulated transcription factors that have proven to be a rich source of targets for development of drugs that target myriad human diseases. The retinoic acid receptor-related orphan receptors (RORs) are members of this superfamily and regulate several physiological processes including the circadian rhythm, metabolism and the immune response. We recently identified the first selective synthetic ligands that target ROR, a critical regulator of the circadian rhythm. Our long-term goal is to develop ligands targeting RORs that can be used to treat diseases associated with dysregulation of the circadian rhythm such as bipolar and sleep disorders as well as schizophrenia. The initial lead compound (T0901317) has less than optimal properties for use as a drug targeting ROR and our preliminary data indicates that we can significantly improve its drug like properties. We hypothesize that optimized ROR ligands, based on the T0901317 chemical scaffold, with improved pharmacodynamic, pharmacokinetic, and receptor selectivity properties will have efficacy in modulation of the circadian rhythm. In order to address this hypothesis we will focus on the following specific aims: 1) Develop and optimize ROR ligands with improved pharmacokinetic and pharmacodynamic properties targeting the central nervous system; 2) Characterize the actions of ROR ligands on the circadian rhythm in animals. We predict that this research will provide novel, innovative ligands that modulate ROR1 activity that will have potential utility to treat sleep disorders as well as other disorders associated with dysregulation of the circadian rhythm including biopolar disorder and schizophrenia. PUBLIC HEALTH RELEVANCE: The nuclear hormone receptor superfamily (NHR) has proven to be a rich source of targets for development of drugs that target myriad human diseases and we recently identified the first selective synthetic ligands for the retinoic acid receptor-related orphan receptors (RORs). This receptor is a key regulator of the circadian rhythm and dysregulation of the circadian rhythm is associated with several disorders of the nervous system including bipolar and sleep disorders. The goal of this proposal is to develop ROR ligands with optimized pharmacodynamic and pharmacokinetic properties and appropriate receptor selectivity profiles that we will evaluate for their ability to modulate circadian function in vivo.